August 10th, 2014
The study, supported by CureDuchenne, may lead to new research paths toward a cure for Duchenne and other related genetic disorders
A new “route forward for therapy” for patients with Duchenne muscular dystrophy, a degenerative disease that mostly afflicts young boys, has been reported by Dr. Kevin Flanigan, principal investigator at the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio. The research, which focuses on developing a therapy for duplication mutations, has resulted in two recent advances. The first was the successful creation of a new mouse model of Duchenne that contains a duplication of exon 2 and the second was the identification of a novel internal ribosome entry site (IRES) within the 5’ coding region of the DMD gene. Taken together, these advances could provide a route forward to therapy.
Dr. Flanigan’s study was published in the journal Nature Medicine, and was supported by funding from CureDuchenne, a national nonprofit that raises awareness and funds research to find a cure for Duchenne muscular dystrophy. Duchenne is a progressive muscle-wasting disease that impacts one in 3,500 boys. Boys are usually diagnosed by age 5, in a wheelchair by 12 and most don’t survive their mid-20s.
Skipping of one copy of exon 2 results in a full length “wild-type” transcript, but skipping of both copies activates the dystrophin IRES, resulting in the expression of a dystrophin isoform that entirely corrects most histopathologic markers of damage in the mouse, and corrects physiologic defects. These results provide Dr. Flanigan’s lab with a pathway forward to treat patients with a duplication of exon 2, and also patients with mutations within the first 5 exons of the gene.
“CureDuchenne really recognized early on the importance of this work and we wouldn’t be here today without the support of their foundation,” said Dr. Flanigan. “They supported the development of the mouse model and supported the personnel to work on this research. It is critical for parents and donors to know that organizations like CureDuchenne vet projects like this and seek out early phase projects in order to play a key role in their development.”
CureDuchenne has always been interested in rare mutations, and was pleased when Dr. Flanigan approached the foundation about funding work on duplication mutations. In 2011, CureDuchenne provided the funding for Dr. Flanigan to create a new Duchenne mouse model with a duplication mutation of exon 2, providing the first animal model in which to directly experiment with exon skipping for duplication mutations. Duplications account for about six percent of mutations in the gene.
“While this is still early stage research, it expands our understanding of the genetic underpinnings of Duchenne and, in turn, helps us uncover new paths toward a cure,” said Debra Miller, CEO and founder of CureDuchenne. “We want a cure for all affected by the disease, and that is why we have supported all duplication and rare mutations. CureDuchenne is pleased to see Dr. Flanigan’s work progress and is proud to continue to support his important work.”